Project Summary Clinicians, patients, and researchers encounter numerous challenges in their efforts to treat chronic pain effectively and safely. Chronic pain affects approximately 1 out of 3 Americans and costs up to $635 billion a year for treatment and lost productivity; the excessive prescription of opioids has escalated into a crisis. Non- opioid pain medications are one alternative treatment method for pain management; however, data on these medications are limited to clinical studies that lacked the power to evaluate safety outcomes appropriately. Despite the crucial role of clinical trials in establishing treatments? efficacy, many drugs have had unforeseen and serious long-term side effects. Pharmacoepidemiologic studies offer the opportunity to study these risks, particularly among vulnerable populations often excluded from clinical trials. We propose three such studies aimed to provide critical information about the cardiovascular risks associated with the use of three widely prescribed non-opioid medications used to treat patients with chronic pain: cyclobenzaprine (muscle relaxant), duloxetine (serotonin-norepinephrine reuptake inhibitor), and pregabalin (analgesic anticonvulsant). We selected these drugs for the following reasons: 1) they are used by millions of patients; 2) multiple case reports raise concern for increased risk of serious cardiovascular events; and 3) their mechanisms of action raise significant concern about cardiovascular toxicity. More specifically, cyclobenzaprine is structurally similar to amitriptyline, a drug widely-recognized to be cardiotoxic; duloxetine raises adrenergic activity, which potentially increases the risk of myocardial infarction. Pregabalin causes significant fluid retention, and thus can exacerbate heart failure. Consequently, there is an immense need to define these drugs? risks, specifically serious cardiovascular outcomes resulting in hospitalization or death. We propose to study Medicare Part D beneficiaries because their increased risks and multiple comorbidities heighten the potential for cardiovascular side effects. With increasing scrutiny and limitations placed on opioid prescriptions (one in three beneficiaries received at least one opioid prescription in 2016), the number of Medicare beneficiaries filling prescriptions for these non-opioid drugs?already in the millions?is likely to increase, despite the lack of high quality long-term safety data. We will use state of the art pharmacoepidemiologic techniques and a large database of Medicare enrollees to assemble a cohort of patients with chronic non-cancer pain. Aim 1 will define the risk for serious cardiovascular outcomes in patients taking cyclobenzaprine. Aim 2 will define the risk of serious cardiovascular events associated with the use of duloxetine. Aim 3 will define the risk of heart failure associated with patients taking pregabalin. These studies will compare those risks with the risk observed in patients with chronic pain taking gabapentin, an anticonvulsant with no clinical signals of cardiovascular side effects.